Maine Researchers Find Possible Clue to Osteoporosis, Obesity

In findings that could lead to new treatment options for osteoporosis and obesity, a research team led by Maine scientists has identified a protein that controls the amount of marrow fat inside bones.

"As we age," says Cheryl Ackert-Bicknell, PhD, a postdoctoral associate at The Jackson Laboratory who was part of the research team, "the red marrow found in long bones is replaced with yellow or fatty marrow. In patients who have suffered an osteoporotic fracture, there are more marrow-residing fat cells as compared to age-matched patients who have never fractured."

In a paper published in the Proceedings of the National Academy of Sciences, the research team led by Clifford Rosen, MD, of the Maine Medical Center Research Institute (MMCRI) showed that mice lacking a protein called nocturnin had less marrow fat and increased bone mass. Likewise, mice with too much nocturnin showed more marrow fat and reduced bone mass.

Another protein known as PPARγ is a key factor that can increase the number of marrow fat cells, especially when activated by drugs such as rosiglitazone, which is used to treat type 2 diabetes. The researchers demonstrated that nocturnin can control PPARγ activity, and thus may control the development of marrow fat.

Rosen, who is director of MMCRI's Center for Clinical and Translational Research, explains that nocturnin is a protein originally found in yeast, where it serves as a cell sensor to respond to nutrient availability. "In our studies of mice," he says, "we found that nocturnin can also sense nutrient availability and, in response to the external environment, stimulate the growth of fat cells." If the organism has a greater supply of certain nutrients, fat cells will expand, and nocturnin may be responsible for those changes, he says.

"What's remarkable about nocturnin," Rosen notes, "is that it's tied to the mouse's mechanism for keeping time, such that it comes on during evening when the mouse consumes food. We have known for some time that alterations in circadian rhythms (for example with certain drugs, or in shift workers) can result in weight gain and excess food consumption. Alterations in nocturnin may be one mechanism to explain this phenomenon.

"In addition, we report that excess nocturnin can lead to a reduction in bone mass. Hence, changes in our circadian networks may have profound effects on body composition and bone density."

Ackert-Bicknell adds, "Increasing our understand of how and why marrow-residing fat cells develop could ultimately lead to increased treatment options for osteoporosis. And, as fat cells elsewhere in the body also express both PPARγ and nocturnin, this work potentially could increase our understanding of obesity."

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community.

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Kawai et al.: A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-γ nuclear translocation. Proceedings of the National Academy of Sciences, published online before print May 24, 2010, doi: 10.1073/pnas.1000788107.